Loss of thioredoxin 2 alters mitochondrial respiratory function and induces cardiomyocyte hypertrophy
Loss of thioredoxin 2 alters mitochondrial respiratory function and induces cardiomyocyte hypertrophy
复制标题
硫氧还蛋白 2 的缺失会改变线粒体呼吸功能并诱导心肌细胞肥大
DOI：
10.1016/j.yexcr.2018.09.010
复制
发表时间：
2018-11-01
影响因子：
3.7
通讯作者：
Yang, Dan
中科院分区：
文献类型：
--
作者：
Hu, Chunyan;Zhang, Hao;Yang, Dan
硫氧还蛋白2（Trx 2）是线粒体硫氧还蛋白系统的一员，参与线粒体氧化还原状态的调控。然而，Trx2在心脏生物学中的作用尚未完全了解。在本研究中，沉默Trx 2的表达在静止的新生大鼠心室心肌细胞（NRVC）和线粒体呼吸功能和心肌细胞肥大进行了评估。结果表明，Trx2耗竭在静止的NRVC中不诱导显著的细胞毒性。值得注意的是，Trx2耗竭导致心肌细胞肥大，如通过增加的细胞大小和蛋白质合成所确定的。此外，Trx2耗竭抑制AMPK活性，AMPK激活剂逆转细胞肥大。Trx2缺失增强线粒体ROS产生而不影响细胞ROS水平。Trx2缺失对线粒体生物合成没有影响。具体而言，Trx2耗竭增加线粒体呼吸通量和总ATP浓度在静止条件下。为了解释ROS产生、线粒体呼吸通量和AMPK信号之间的关系，线粒体代谢和ROS被特异性抑制，结果表明，呼吸阻断剂而不是ROS清除剂逆转了Trx2沉默细胞中AMPK失活和肥大反应。总之，这些结果表明，除了线粒体ROS清除，Trx2控制静止心肌细胞中的线粒体呼吸功能，并通过AMPK信号转导参与心肌细胞肥大。
Thioredoxin 2 (Trx2), as a member of the thioredoxin system in mitochondria, is involved in controlling mitochondrial redox state. However, the role of Trx2 in cardiac biology is not fully understood. In the present study, the expression of Trx2 is silenced in quiescent neonatal rat ventricular cardiomyocytes (NRVCs) and mitochondrial respiratory function and cardiomyocyte hypertrophy are assessed. The results show that Trx2 depletion does not induce significant cytotoxicity in quiescent NRVCs. Remarkably, Trx2 depletion results in cardiomyocyte hypertrophy as determined by increased cell size and protein synthesis. Furthermore, Trx2 depletion inhibits AMPK activity and AMPK activator reversed cellular hypertrophy. Trx2 depletion enhances mitochondrial ROS generation without impact on cellular ROS level. Trx2 depletion has no effect on mitochondrial biogenesis. Specifically, Trx2 depletion increases mitochondrial respiration flux and total ATP concentration under quiescent conditions. To decipher the relationship between ROS generation, mitochondrial respiration flux, and AMPK signaling, mitochondrial metabolism and ROS was specifically inhibited, and the results show that AMPK inactivation and hypertrophic response in Trx2-silenced cells is reversed by respiration blockers but not ROS scavenger. In conclusion, these results show that beyond mitochondrial ROS scavenging, Trx2 controls mitochondrial respiratory function in quiescent cardiomyocytes and is implicated in cardiomyocyte hypertrophy via AMPK signaling.